This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic nephropathy, with the exception of the genetics of diabetic nephropathy, is now reported under this single project. In the last year, we contributed data to an international consortium that reported on the predictive value of low estimated glomerular filtration rate and elevated albuminuria for mortality and kidney outcomes. This collaboration resulted in two publications in Kidney International, which described the association of these variables with all-cause and cardiovascular mortality and with kidney disease in high-risk population cohorts. Another paper published in the Journal of the American Medical Association compared risk prediction for mortality and kidney disease using either the CKD-EPI equation or the MDRD Study equation for estimating glomerular filtration rate. This study found that the newer CKD-EPI equation provided better prediction of these health outcomes. Two papers are presently in press at the Lancet, which describe how blood pressure and diabetes modify the associations between estimated glomerular filtration rate, urinary albumin excretion, and health outcomes including all-cause mortality, cardiovascular mortality, and kidney failure. In general, we found that the relative risks of mortality and kidney failure are similar regardless of the presence or absence of diabetes or hypertension, emphasizing the importance of kidney disease per se as a predictor of health outcomes. In the coming year, this consortium will look at how age, sex, and ethnicity modify the effects of estimated glomerular filtration rate and urinary albumin excretion on these health outcomes. Last year, we developed morphometric methods to quantify podocyte detachment from the basement membrane and the number of endothelial fenestrae in glomerular endothelial cells. In a paper presently in press at Kidney International, we reported that these variables correlate strongly with other structural and functional characteristics of diabetic nephropathy, and we confirm the important role that these distinct cellular injuries play in the development and progression of diabetic glomerular disease. In another paper published in the Clinical Journal of the American Society of Nephrology, we examined the predictive value of early renal function decline for later development of end-stage renal disease. We found that renal function decline was frequent in type 2 diabetes, and its prevalence was higher with greater degrees of albuminuria. We reported that the appearance of renal function decline often preceded the appearance of macroalbuminuria or even microalbuminuria, confirming that it is an early event in diabetic kidney disease. However, a decline in kidney function predictive of end-stage renal disease was strongly dependent on progression to macroalbuminuria, suggesting the clinical value of ascertaining GFR slopes to predict progressive kidney disease in patients with normal urinary albumin excretion or microalbuminuria is limited. In a paper now in press at Diabetes, we examined glomerular gene expression profiles in persons with early type 2 diabetes and in three mouse models of diabetic kidney disease for the purpose of identifying shared human-mouse cross-species glomerular transcriptional networks. A number of shared networks were identified, which may assist researchers in the selection of mouse models most relevant to the specific pathway to diabetic nephropathy of interest and it will allow identification of new pathways shared between mice and humans. One clinical trial is presently underway as part of this project. The clinical trial is a single-center randomized, double-blinded, placebo-controlled study involving 170 adults with type 2 diabetes and normal urinary albumin excretion or microalbuminuria. It was designed to determine whether blockade of the angiotensin II receptor with losartan will prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care. Subjects in each albumin excretion group were randomized to treatment with either losartan, or placebo. Measurements of glomerular filtration rate, renal plasma flow and fractional clearances of albumin and IgG were made using standard urinary clearance methods. These tests were performed initially, at one month, and at 12-month intervals from baseline thereafter. The primary outcome measure is a decline in GFR to less than 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of <120 ml/min. A kidney biopsy was performed after 6 years in 122 of these subjects. Morphometric analysis of kidney biopsies was used to determine differences in glomerular structure between treatment groups. We completed the randomized treatment portion of the losartan clinical trial five years ago and the laboratory assays of glomerular filtration rate and renal plasma flow two years ago. Morphometric analyses on the kidney biopsies were completed earlier this year, and we are now preparing a manuscript that describes the findings of this clinical trial. Over the past two years, we worked with the National Kidney Foundation to update the guidelines for management of patients with diabetes and kidney disease, and the guideline update will be published in November 2012 in the American Journal of Kidney Diseases. This project continues to yield many new insights into the pathogenesis, course, and treatment of kidney disease in type 2 diabetes. Much work in the past year has gone into measuring potential biomarkers that predict the development and progression of diabetic kidney disease, and results from this work should be available by next year.